Not All SCN1A Epileptic Encephalopathies Are Dravet Syndrome Early Profound Thr226met Phenotype

Not all SCN1A epileptic encephalopathies are Dravet syndrome Early profound Thr226Met phenotype

Lynette G. Sadleir, ABSTRACT MBChB, MD Objective: To define a distinct SCN1A developmental and epileptic encephalopathy with early Emily I. Mountier, BSc onset, profound impairment, and movement disorder. (Hons) Methods: A case series of 9 children were identified with a profound developmental and epileptic Deepak Gill, FRACP encephalopathy and SCN1A mutation. Suzanne Davis, MBChB, PhD Results: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 Charuta Joshi, MBBS weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had pro- Catherine DeVile, MBBS, found developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required MD* a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dys- Manju A. Kurian, PhD* tonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. SCN1A For the DDD Study* Eight had a recurrent missense mutation, p.Thr226Met. The remaining child had the Simone Mandelstam, missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, MBChB the mother was negative and the father was unavailable. Elaine Wirrell, MD Conclusions: Here, we present a phenotype-genotype correlation for SCN1A. We describe a dis- Katherine C. Nickels, tinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable MD from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures Hema R. Murali, MBBS, plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinc- MD tive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 Gemma Carvill, PhD children had the recurrent missense mutation p.Thr226Met. Neurology® 2017;89:1035–1042 Candace T. Myers, PhD Heather C. Mefford, MD, GLOSSARY PhD GEFS1 5 genetic epilepsy with febrile seizures plus. Ingrid E. Scheffer, MBBS, PhD The finding of de novo SCN1A mutations in Dravet syndrome was paradigm shifting in our understanding of the etiology of the developmental and epileptic encephalopathies.1,2 Less commonly, inherited SCN1A mutations occur in the self-limiting familial epilepsy syndrome Correspondence to 1 3 Dr. Sadleir: of genetic epilepsy with febrile seizures plus (GEFS ). Missense and truncation mutations are [email protected] found in approximately equal frequency in Dravet syndrome, while GEFS1 is largely associated or Dr. Scheffer: 4 . [email protected] with missense mutations. Despite 1,200 reported SCN1A mutations and most patients having novel mutations, there are no clear phenotype-genotype correlations. We have identified a distinctive SCN1A developmental and epileptic encephalopathy that is far more severe than Dravet syndrome and is associated with a recurrent missense mutation. It is Supplemental data at Neurology.org From the Department of Paediatrics and Child Health (L.G.S., E.I.M.), University of Otago, Wellington, New Zealand; Department of Neurology (D.G.), University of Sydney, Australia; Department of Neurology (S.D.), Starship Children’s Health, Auckland, New Zealand; Department of Neurology (C.J.), Children’s Hospital Colorado, Anschutz Medical Campus, University of Colorado, Denver; Department of Neurology (C.D.V., M.A.K.), Great Ormond Street Hospital for Children; Developmental Neurosciences (M.A.K.), UCL Great Ormond Street Institute of Child Health, London; Wellcome Trust Sanger Institute (DDD Study Group), Hinxton, Cambridge, UK; Departments of Paediatrics and Radiology (S.M.), University of Melbourne; The Florey Institute of Neuroscience and Mental Health (S.M., I.E.S.); Department of Medical Imaging (S.M.), Royal Children’s Hospital, Melbourne, Australia; Department of Neurology (E.W., K.C.N.), Mayo Clinic, Rochester, MN; Department of Neurology (H.R.M.), Marshfield Clinic, WI; Division of Genetic Medicine (G.C., C.T.M., H.C.M.), Department of Pediatrics, University of Washington, Seattle; and Departments of Medicine and Paediatrics (I.E.S.), University of Melbourne, Austin Health and Royal Children’s Hospital, Australia. *Authors in the DDD Study Group. Coinvestigators are listed at Neurology.org. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. The Article Processing Charge was funded by Wellcome Trust. This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Table Clinical features and investigations of children with early infantile SCN1A encephalopathy

Case (sex/age)

1 (M/8 y) 2 (M/6 y) 3 (M/9 y)5 4 (M/8 y)5 5 (M/9 y) 6 (M/10 y)2 7 (F/1 y) 8 (F/3 y) 9 (M/12 y)6

Mutation c.677C.T, c.677C.T, c.677C.T, c.677C.T, c.677C.T, c.677C.T, c.677C.T, c.677C.T, c.4033C.T, p.Thr226Met de p.Thr226Met de novo p.Thr226Met; p.Thr226Met de novo p.Thr226Met de p.Thr226Met de p.Thr226Met de p.Thr226Met de novo p.Pro1345Ser de novo mother negative, novoa novo novo novo father unknown

Sz onset age 12 wk; HC-SE 9 wk; HC-SE 9 wk; HC-SE 8 wk; TC-SE 11 wk; TC (8 y) 8 wk; HC (died–10 12 WK; HC; 6 wk; ES 8 wk; HC; possible erlg 9Spebr5 2017 5, September 89 Neurology (offset) y, SUDEP) possible ES–8wk ES–6wk

Other Sz onset 18 mo–TC, T; 2 y– 3mo–TC, M, F; 2 y– 18 mo–TC; 4 y–T, 9wk–HC; 21 mo–M; 3 7y–T9mo–TC, F, SE; 6mo–SE; 12 mo– 10 wk–HC, F; 6 mo– 10 wk–TC, ES; 6 mo– age Ab; 3 y–M; ES; 5 y–F, ES, NCS At; 7 y–NCS y–Ab, NCS; 5 y–MA M, 13 mo–T M, TC, F TC, SE; 7 mo–M M; 1 y–Ab; 2 y–SE, F; NCS 5y–T

Sz triggers M: sound and Excitement and water; T: fever and feeding Fever, illness, and hot Bowel movements Fever Fever, excitement, Fever T: excitement, noise, wakening ES: feeding and environment and light, and hot drinking overstimulation environment

MD onset 11 mo 3 mo 9 wk 20 mo ,6mo 9mo 4mo 11mo 11mo

MD description Hyperkinesis; Dystonia; Continuous Dystonia; Hyperkinesis, Continuous Continuous Continuous Hyperkinesis; dystonia; choreoathetosis myoclonic choreoathetosis; especially orofacial; multifocal hyperkinesis and choreoathetosis, choreoathetosis; choreoathetosis including orofacial; movements, continuous unilateral myoclonic myoclonic chorea; multifocal myoclonic myoclonic limbs and orofacial exacerbated by especially orofacial; horizontal nystagmus; movements; movements; exacerbated by movements; movements, excitement and exacerbated by myoclonic movements; dystonia; nystagmus, overstimulation exacerbated by especially orofacial bathing; severely visual stimuli; profound ataxia nystagmus; vertical and tiredness, drowsiness, tremulous on waking tremulous on stereotypies; horizontal and waking waking exacerbated by tiredness and excitement

Age DD noted 4mo 9wk 9wk 9wk 6wk 9wk 3mo 10wk 8wk

Development NV, communicates NV but vocalizes, NA– NV, NA–sits with NV, NA–stands with NV, NA–sits with NV–smiles, NA, G- NV, NA, G-tube NV, NA, G-tube Only 2 single words, outcome with facial gestures, stands with support support, G-tube support, G-tube support tube NA, G-tube smiles and sounds; NA, G-tube

Medication trials KD, PHT, LEV, TPM, VGB, CZP, VPA, PB, CBZ, VPA, CLB, PB, PHT, TPM, VPA, VPA, LTG, PB, PHT, PB, VPA, CBZ, PB, OX, GP, LEV, PB, PRD, ACTH, TPM, CBZ, PB, VGB, VPA, NZP, CZP, PB steroids, PB, LTG, KD CZP, RFM, ETX, AZD, CLB, TPM, LEV PHT, ACTH, CLB, CBD, KD, TPM, LEV, KD, CZP, CLB, PHT, CLB, LTG, LEV, CLB, TPM steroids, LEV, STP, TPM, CZP, LEV, CLB, VPA DZP steroids, LEV, KD, CBD, KD STP cannabis oils

Examination Hypertelorism, high Axial hypotonia; Hypotonia Hypotonia Microcephaly; axial Spasmus nutans; Axial hypotonia; Hypotonia Axial hypotonia; forehead, small variable limb tone hypotonia; variable tone increased at hypertonia of limbs variable limb tone mouth; axial limb tone with brisk 3 mo but hypotonia; variable reflexes; scoliosis hypotonic later limb tone; kyphoscoliosis

Continued 5 5 characterized by early infantile seizure onset, profound intellectual disability, and a severe nonverbal;

6 hyperkinetic movement disorder. This recur- gabapentin; 5 5 rent SCN1A mutation shows clear genotype- myoclonic seizure; clonazepam; DD phenotype correlation. 5 9 (M/12 y) 1 and 1.5 y:MFD N; and 2 slow; y: 2.5GSW y: and slow; 3MFD y: and slow; 5bifrontal y: spike and wave in runs and slow; 10 y: MFDslow and Small hippocampi; dysmorphic corpus callosum 5 stiripentol; SUDEP

5 METHODS Case 1 presented with an early infantile profound developmental and epileptic encephalopathy. Because he had hemiclonic seizures, the senior author (I.E.S.) requested SCN1A

lamotrigine; M testing that revealed a de novo missense variant (Thr226Met). clobazam; CZP 5 Because this phenotype was distinctive, we interrogated the Epi- 5 lepsy Genetics Database at the University of Melbourne, which 10 and 12 wk:and MFD slow; 9 mo: FD;and12 11 mo: MFD and slow; 21 mo: ESES Generalized atrophy; R mesial temporal sclerosis; temporal arachnoid cysts 8 (F/3 y) contained 981 individuals with solved and unsolved developmen- status epilepticus; STP focal epileptiform discharges; GP tal and epileptic encephalopathies tested for SCN1A mutations. 5 5 We searched for children with de novo SCN1A variants who nonconvulsive status epilepticus; NV presented at ,4 months of age and had a movement disorder. 5

levetiracetam; LTG All identified patients were included. This identified 3 additional 5 carbamazepine; CLB cases: cases 2 and 6 with the Thr226Met variant and case 9 with 5 8 wk, 12 wk,mo: and N; 6 15 mo andy: 5 MFD and slow; 10 y: GSW Generalized atrophy; bilateral small hippocampi 7 (F/1 y) the Pro1345Ser variant. Because 3 of the 4 cases had the valproate. rufinamide; SE Thr226Met variant, we searched our database and the literature 5 5 for other cases with this variant and attempted to contact the 2

other focal seizure; FD authors for more phenotypic information. This resulted in an

5 5

nonambulatory; NCS additional 2 cases (cases 3 and 4). The final 3 cases (cases 5, 7, ketogenic diet; LEV 5 cannabidiol; CBZ and 8) were recruited when collaborators asked the first (L.G.S.) 5 Small hippocampi, 9 wk: FD; 15MFD mo: and slow; 2 y: PSW and slow; 3 y: MFD, periods of attenuation L hippocampus malrotated; progressive white matter atrophy 6 (M/10 y) 5 and senior (I.E.S.) authors about the role of the de novo SCN1A vigabatrin; VPA

5 Thr226Met variant that they had identified in their patients who presented with an atypical phenotype for Dravet syndrome. normal; NA

ethosuxamide; F Epilepsy and medical history, neurologic examination, polyspike and wave; RFM 5 5 and MRI and EEG data were obtained for each patient. 5 SCN1A mutations were identified by clinical or research test- N 14 mo: FD; 2y: and MFD 8 and slow 5 (M/9 y)

acetazolamide; CBD ing; segregation testing in parents was possible for 8 topiramate; VGB 5

5 individuals. hippocampal sclerosis; KD

5 Standard protocol approvals, registrations, and patient consents. The Austin Health Human Research Ethics Commit- 5 prednisolone; PSW tee and the New Zealand Health and Disability Ethics Commit- 5 tees approved the study. Informed consent was obtained for each Pineal cyst 10, 14, 19, 20 mo2 and y: MFD, GSW,slow; and 5 y: atypical GSW, ESES; 6 y:ESES, MFD, and slow 4 (M/8 y) patient from the parents or legal guardian. In addition, specific atonic seizure; AZD written consent for authorization of video use was obtained for 5 the 3 cases in the video. tonic-clonic seizure; TPM hemiclonic seizure; HS 5 multifocal epileptiform discharges; N 5 phenytoin; PRD electric status epilepticus in sleep; ETX 5

5 RESULTS We identified 9 (7 boys) unrelated chil- 5 5 dren 3 to 12 years of age (table). They presented with 3 (M/9 y) L temporal fossa arachnoid cyst 3 mo: FD and1, slow; 1.5, 4.5, andMFD 7 and y: slow seizures at a mean age of 9 weeks (range 6–12 weeks) with predominantly hemiclonic seizures (n 5 6) but

tonic seizure; TC also with bilateral tonic-clonic seizures (followed 1 5 week later by hemiclonic seizures in 1 patient) or gastrostomy tube; HC 5 phenobarbitone; PHT epileptic spasms. All children developed tonic-clonic adrenocorticotropic hormone; At 5 epileptic spasms; ESES

5 seizures by 18 months. Eight had episodes of con- seizure; T movement disorder; MFD 5 2 (M/6 y) Small hippocampi at 1 y; developed bilateral enlarged hippocampi, L malrotated 2, 2.5, and 4and mo: 3 N; y: 2 MFDslow; and 3 y: briefof bursts rhythmic fast bitemporal activity triggered by the placement of food in mouth 5

5 vulsive status epilepticus with onset between 8 weeks and 2 years (table). Myoclonic seizures (7 of 9), tonic seizures (5 of 9), and spasms (5 of 9) were also seen. Epilepsy was refractory to multiple antiepileptic diazepam; ES 5 oxcarbazepine; PB medications in all cases, although 1 child became 5 seizure free at 8 years. Five children had seizures Small hippocampi, developed L HS; dysmorphic corpus callosum; progressive white matter volume atrophy 4 mo, 9 mo, 11 mo,y, 4 and 6 y;slow MFD and Case (sex/age) 1 (M/8 y) absence seizure; ACTH

5 associated with fever or illness, and 2 children had seizures exacerbated by high environmental temper- Continued ature. There were no reports of vaccination triggering mutation identified via the DDD Study Group. generalized spike and slow wave; G-tube nitrazepam; OX myoclonic absence seizure; MD seizures. Other seizure triggers included auditory 5 5 5 stimuli (2), excitement (3), feeding (2), and bowel MRI EEG Table SCN1A MA NZP Abbreviations: Ab a GSW sudden unexplained death in epilepsy; Sz developmental delay; DZP movements (1).

Neurology 89 September 5, 2017 1037 Initial development was considered normal by all discontinuation of the medication had no effect on parents, who gave reports of normal early develop- the movement disorder. There was also no clear exac- mental milestones. Delay was evident, however, by erbation of their seizures with these medications; 6 to 16 weeks. At last review (range 3–12 years), 8 however, their seizures were so frequent that it may children were nonverbal, and 1 child spoke 2 single have been difficult to assess. words. All were nonambulatory, and 7 required Neuroimaging was normal or showed nonspecific enteral feeding. The children had periods of regres- abnormalities. Four children had developmentally sion or developmental plateauing resulting in pro- abnormal hippocampi; 2 had dysmorphic corpus cal- found intellectual disability. One child died at 10 losal; and 2 had progressive white matter loss (table years of sudden unexplained death in epilepsy. and figure). EEGs were initially normal in 3 children, All patients had a prominent movement disorder but by 2 years of age, all had developed multifocal that developed within the first 2 years of life (9 discharges and diffuse background slowing. Four chil- weeks–20 months). Initially, they presented with dren had generalized spike and slow wave or poly- subtle, low-amplitude myoclonic jerks. Over time, spike and slow wave. a hyperkinetic movement disorder comprising cho- All patients had SCN1A mutations; 8 were con- rea, dystonia, and low-amplitude myoclonic move- firmed de novo. The mother of case 3 was negative, ments was noted, particularly evident in the and the father was unavailable. Cases 1, 2, and 9 were orofacial area (video at Neurology.org). Although identified on molecular inversion probe–targeted re- not always present, the movement disorder was per- sequencing6; cases 3, 4, and 8 were identified on sistent and exacerbated on awakening and excite- clinical panels; case 5 was identified on whole-exome ment. The abnormal movements were not seen sequencing; and cases 6 and 7 were identified by during sleep. EEG recordings showed no epileptiform SCN1A sequencing. No additional likely pathogenic activity with these movements. variants were found in other genes in the cases that Eight of our 9 cases were trialed on antiepileptic had targeted resequencing, clinical panels, or whole- drugs that could induce or exacerbate movement dis- exome sequencing. Eight children had the same mis- orders or myoclonic seizures such as vigabatrin or sense mutation, p.Thr226Met, resulting from sodium channel blockers (e.g., phenytoin, carbamaze- c.677C.T in exon 5. In silico tools suggested that pine, oxcarbazepine, lamotrigine). In several cases, it was deleterious (Grantham D 5 81, Polyphen2 5 these drugs were begun well after the movement dis- 1, SIFT 5 0, GERP 5 5.77, CADD 5 20.5). The order had been recognized. Subsequent ninth child had a de novo missense mutation,

Figure MRI in children with early infantile SCN1A encephalopathy

(A–C) Coronal views in case 1 (3 years of age), case 9 (5 years of age), and case 2 (1 year of age) show bilateral small hippocampi. (A) Case 1 developed left hippocampal sclerosis. (C) Case 2 has a malrotated left hippocampus. (D, F) Axial T2 and coronal T1 images of case 9 show (D) normal white matter volume at 2 months of age with (F) moderately severe volume loss at 2 years. (E) Coronal views of the hippocampi at 2 months show bilateral small hippocampi with left hippocampal malrotation.

1038 Neurology 89 September 5, 2017 p.Pro1345Ser (c.4033C.T), which was pathogenic activity with background slowing. At 4 months, MRI on in silico testing (Grantham D 5 74, Polyphen2 5 brain revealed bilateral small hippocampi with a dys- 1, SIFT 5 0, GERP 5 5.42, CADD 5 23.7). morphic corpus callosum. By 3 years, he had developed left hippocampal sclerosis and progressive CASE HISTORIES Case 1. Case 1 is an 8-year-old white matter atrophy (figure, A). boy who presented at 12 weeks of age with afebrile hemiclonic status epilepticus lasting 30 minutes. Case 2. Case 2 is a 6-year-old boy who presented at 9 Frequent pharmacoresistant hemiclonic seizures last- weeks with 5 independent afebrile right and left ing 1 minute to 6 hours occurred daily. The lateral- hemiclonic seizures lasting from 1 to 20 minutes over ization of the clonic activity varied and occasionally a 2-hour period that were treated with buccal and migrated from 1 upper limb, to hemiclonic, to both intravenous midazolam and intravenous phenytoin. lower limbs, to hemiclonic on the other side. Bilateral Occasional hemiclonic seizures continued despite the tonic-clonic and tonic seizures began at 18 months, introduction of phenobarbital and topiramate. He absence seizures at 2 years, and myoclonic seizures or developed myoclonic, focal impaired awareness and epileptic spasms at 3 years. By 5 years, he developed bilateral tonic-clonic seizures by 13 weeks. The seiz- focal impaired awareness seizures that could progress ures were not associated with fever but were more to nonconvulsive status epilepticus lasting hours, likely to occur on waking. At 13 weeks, he developed frequent nocturnal tonic seizures, and weekly series of a periodic movement disorder initially lasting 10 to epileptic spasms. Seizures were triggered by waking 30 minutes consisting of choreoathetosis, dystonia, but not by illness or fever. He has had multiple and small-amplitude myoclonic jerks, which his pa- hospital admissions for status epilepticus and poor rents called “dancing.” This was triggered by waking seizure control, the longest a 3-month admission at and excitement, particularly bathing. His movement 18 months. Trials of phenobarbital, phenytoin, ni- disorder progressed over the next 18 months so that trazepam, clonazepam, levetiracetam, and topiramate by 2 years it occurred almost continuously, although were ineffective. The ketogenic diet was initiated at 4 it settled in sleep. He did, however, have massive years and resulted in improved control with cessation myoclonic jerks without EEG correlate on awaken- of myoclonic seizures. By 8 years, he was on ketogenic ing. His epilepsy was refractory to sodium valproate, diet monotherapy and continued to have weekly lamotrigine, and levetiracetam. From 2 years, he had tonic-clonic, focal impaired awareness, and tonic infrequent episodes of focal nonconvulsive status seizures in sleep and required admission every few epilepticus, characterized by loss of awareness, eye months. deviation, and facial twitching, lasting up to 2 hours. From birth, he had significant early feeding diffi- The EEG showed high-voltage rhythmic focal delta culties. Developmental milestones were otherwise in the centro-parietal region. At 2.5 years, he devel- normal with good head control, smiling, and fixing oped flexor epileptic spasms when eating or drinking. and following by 6 weeks. From 4 months, his devel- The spasms occurred every 10 to 20 seconds for opment plateaued and fluctuated over the next few 3 minutes shortly after food or liquid was put in his years with regression between 3 and 4 years. He lost mouth and interfered with his ability to chew and eye contact, smiling, vocalization, head control, and swallow. The spasms were controlled for 2 months the ability to roll over. He required a gastrostomy but then relapsed and are ongoing. By 4 years, the for feeding. When he was initiated on the ketogenic massive myoclonic jerks were awakening him over- diet at 4.5 years, he had a marked improvement in night, which triggered his movement disorder and alertness and developmental gains. At 8 years, he prevented him from sleeping, posing a major problem smiled, laughed, and vocalized vowel sounds but for the family’s quality of life. was nonverbal. He did not feed orally. He was able His development was normal at 9 weeks; he smiled to roll over but could not sit. and fixed and followed by 6 weeks. Within a week of He developed a hyperkinetic movement disorder seizure onset, he regressed with loss of visual fixation by his first birthday consisting of choreiform move- and head control. By 5 months, he was rolling over, ments including the orofacial area, dystonic posturing and by 8 months, he was sitting and finger-feeding. of the upper and lower limbs, and myoclonus without After 9 months, his development plateaued with EEG correlate (video). Video monitoring at 16 a period of regression at 2 years. At 6 years, he vocalizes months confirmed that all the abnormal movements but is nonverbal, nor can he sit or walk independently. did not have an epileptiform correlate. He has normal On examination, he was not dysmorphic and had tone in his limbs with reduced truncal tone. He has almost continuous choreiform movements involving hypertelorism, a high forehead, a small mouth, a nor- the limbs and orofacial region (video). His limb tone mal head circumference, and a mild kyphoscoliosis. was variable with axial hypotonia. Early EEGs EEGs from 4 months showed multifocal epileptiform between 10 weeks and 4 months were normal, but

Neurology 89 September 5, 2017 1039 multifocal epileptiform abnormalities had developed epilepsy; however, the limited available clinical infor- by 2 years. MRI at 1 year showed bilateral small mation suggests that the phenotype of this child could hippocampi with left hippocampal malrotation be consistent with early infantile SCN1A encephalop- (figure, C). athy.8 Overlap between the movement disorder and a progressive myoclonus epilepsy could be challeng- DISCUSSION SCN1A is the most relevant epilepsy ing to distinguish, especially given that the patient gene. Despite considerable effort, no phenotype- was middle-aged at the time of review. The remaining genotype correlation has been shown for the hun- child presented with febrile status epilepticus at dreds of SCN1A mutations identified, with the 6 months.2 However, she then developed extensor majority associated with Dravet syndrome and a small epileptic spasms at 10 months, which would be proportion with GEFS1.4 Here, we show a pheno- extraordinary for Dravet syndrome.7 This patient type-genotype correlation for SCN1A describing was not reported to have a movement disorder, but a distinct SCN1A phenotype, early infantile SCN1A at 9 months, she had continuous myoclonic activity encephalopathy, that is far more severe than Dravet diagnosed as nonconvulsive status epilepticus. This syndrome. We bring together novel cases and rean- could be a differential diagnosis of the movement alyze the phenotype of reported cases with the disorder in our patients, but overall, she had better recurrent mutation to identify a distinctive entity of developmental progress. She also had an SCN9A variant early-onset developmental and epileptic encephalop- (p.W1538R) that may have modified her phenotype.9 athy with profound impairment and a prominent Perhaps this caused loss of function of SCN9A,which movement disorder. in some way modified the functional alteration due to Early infantile SCN1A encephalopathy can be the SCN1A Thr226Met mutation. readily distinguished from Dravet syndrome by sev- The Thr226Met mutation is not the only SCN1A eral features. It has a younger age at onset, beginning mutation described at this specific codon. There are 2 at ,3 months compared with the typical seizure reports of missense SCN1A mutations at codon c.677 onset age range of 4 to 15 months in Dravet syn- that result in a different amino acid change to drome. It is associated with profound developmental Thr226Arg or Thr226Lys.10,11 Not enough clinical impairment rather than the severe to mild intellectual information is provided in the reports to allow assess- disability usually seen in Dravet syndrome. Infantile ment of whether these children have a similarly pro- movement disorders are not part of the Dravet phe- found phenotype. notype, whereas our patients have a distinctive move- A Japanese group has previously described a single ment disorder with choreoathetosis, dystonia, and case of infantile epileptic encephalopathy with perioral hyperkinesia. Other features differentiating a hyperkinetic movement disorder and hand stereoty- early infantile SCN1A encephalopathy from Dravet pies associated with a different novel SCN1A muta- syndrome are epileptic spasms, which are not seen in tion.12,13 This Japanese child’s presentation sounds Dravet syndrome. Tonic seizures are described in like early infantile SCN1A encephalopathy in terms adults with Dravet syndrome but are not part of the of seizure onset age of 8 weeks; seizure types included childhood phenotype.7 epileptic spasms, hemiclonic seizures, myoclonic seiz- We describe that the Thr226Met mutation is ures, generalized tonic-clonic seizures, and status epi- associated with a distinctive profound SCN1A lepticus, with profound impairment. The child also encephalopathy. Three of the 8 patients with had an early-onset severe hyperkinetic movement dis- Thr226Met (cases 3, 4, and 6) have been previously order and a different SCN1A missense mutation reported as having Dravet syndrome.2,5 Case 6 was (c.1264 G.T, p.Val422Leu) from that found in identified in 2007 in our large study delineating the our cohort.12,13 phenotypic spectrum of Dravet syndrome.2 Cases 3 Despite there being .1,200 different reported and 4 were drawn from a 2014 study of sleep prob- SCN1A mutations, only 18% of mutations are recur- lems associated with SCN1A-confirmed Dravet syn- rent.4 Mutations associated with GEFS1 are more drome,5 but the phenotype was not described in the likely to have a lower Grantham score than those that report. The phenotype, early infantile SCN1A cause Dravet phenotypes.4,14 Missense mutations in encephalopathy, was not yet recognized, and the pore region lead to complete loss of function, Dravet-like features such as hemiclonic seizures led similar to haploinsufficiency, but are seen in both to the diagnosis of Dravet syndrome. We have rean- Dravet syndrome (54%) and GEFS1 (31%).4 It is alyzed the phenotype of these patients, and all share therefore not usually possible to predict an individu- a homogeneous profound phenotype. al’s phenotype on the basis of their specific SCN1A In addition, there are 2 further individuals re- mutation. Here, however, we have identified a severe- ported with the Thr226Met mutation.2,8 One is striking SCN1A phenotype, early infantile SCN1A a child described as having progressive myoclonus encephalopathy, that has a recurrent mutation at

1040 Neurology 89 September 5, 2017 c.677 in almost all cases. Somewhat counterintui- STUDY FUNDING tively, this more severe phenotype is associated with Supported by the Health Research Council of New Zealand, Cure Kids missense, rather than truncation, mutations. New Zealand, the Ted and Mollie Carr Endowment Trust, the NIH (National Institute of Neurologic Disorders and Stroke), and the There is increasing recognition of the overlap of National Health and Medical Research Council of Australia. The developmental epileptic encephalopathies and move- DDD Study presents independent research commissioned by the Health ment disorders. Severe hyperkinetic (dystonia, chor- Innovation Challenge Fund (grant HICF-1009-003); see Nature. 2015; 519:223-238 or www.ddduk.org/access.html for full acknowledgement. eoathetosis, myoclonus) movements have been described in a range of genetic encephalopathies DISCLOSURE caused by SCN2A, SCN8A, FOXG1, STXBP1, L. Sadleir serves on the epilepsy advisory board for Nutricia. A/Prof. – GNAO1, ARX, and DNM1, among others.12,15 17 Sadleir and E. Mountier are funded by Health Research Council of Distinguishing a movement disorder from seizures New Zealand grant 15/070, Cure Kids, and the Ted and Mollie Carr may affect therapeutic approaches in terms of when Endowment Trust. E. Mountier and D. Gill report no disclosures relevant to the manuscript. S. Davis has received Food and Drug Adminis- to introduce antiepileptic therapy or other treatment tration funding (1RO1FD004147-01A1; ClinicalTrials.gov identifier modalities. NCT01720667). C. Joshi, C. DeVile, M. Kurian, S. Mandelstam, There is a large group of early-onset developmen- E. Wirrell, K. Nickels, and H. Murali report no disclosures relevant to the manuscript. G. Carvill is a member of the scientific advisory board tal and epileptic encephalopathies defined by their of Ambry Genetics. C. Myers reports no disclosures relevant to the man- onset age of ,3 months, often not fitting within uscript. H. Mefford is funded by NIH grant NINDS 1R01NS069605. a recognized epilepsy syndrome. These disorders have I. Scheffer serves on the editorial boards of Neurology® and Epileptic been recently associated with a large, heterogeneous Disorders and has served on the editorial board of Annals of Neurology Epilepsy Currents; has received revenue from Medvet Science and Bio- 18 range of genetic etiologies. They share many com- nomics for patents; serves on the epilepsy advisory board for Nutricia; mon features such as multiple seizure types, profound may accrue future revenue on a pending patent on therapeutic com- to severe developmental delay, and movement disor- pound; has received speaker honoraria from Athena Diagnostics, UCB, ders. It is unlikely that the seizures or the treatment GSK, Eisai, and Transgenomics; has received funding for travel from Athena Diagnostics, UCB, and GSK; and receives/has received research per se cause the profound developmental impairment support from the National Health and Medical Research Council, or movement disorders, given that a similar spectrum Australian Research Council, NIH, Health Research Council of New of seizure types with onset in later infancy or child- Zealand, March of Dimes, Weizmann Institute, Citizens United for Research in Epilepsy, US Department of Defense, and Perpetual Char- hood does not have the same developmental sequelae. itable Trustees. Go to Neurology.org for full disclosures. For example, infants with the self-limited “benign” early infantile seizure disorders may have frequent Received January 17, 2017. Accepted in final form June 16, 2017. seizures with an abnormal EEG but without the long-term sequelae. 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1042 Neurology 89 September 5, 2017 Not all SCN1A epileptic encephalopathies are Dravet syndrome: Early profound Thr226Met phenotype Lynette G. Sadleir, Emily I. Mountier, Deepak Gill, et al. Neurology 2017;89;1035-1042 Published Online before print August 9, 2017 DOI 10.1212/WNL.0000000000004331

This information is current as of August 9, 2017

Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. Updated Information & including high resolution figures, can be found at: Services http://n.neurology.org/content/89/10/1035.full

Supplementary Material Supplementary material can be found at: http://n.neurology.org/content/suppl/2017/08/09/WNL.0000000000004 331.DC1 http://n.neurology.org/content/suppl/2017/08/09/WNL.0000000000004 331.DC2 References This article cites 18 articles, 1 of which you can access for free at: http://n.neurology.org/content/89/10/1035.full#ref-list-1 Citations This article has been cited by 1 HighWire-hosted articles: http://n.neurology.org/content/89/10/1035.full##otherarticles Subspecialty Collections This article, along with others on similar topics, appears in the following collection(s): All Clinical Neurology http://n.neurology.org/cgi/collection/all_clinical_neurology All Movement Disorders http://n.neurology.org/cgi/collection/all_movement_disorders All Pediatric http://n.neurology.org/cgi/collection/all_pediatric Epilepsy semiology http://n.neurology.org/cgi/collection/epilepsy_semiology Permissions & Licensing Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/about/about_the_journal#permissions Reprints Information about ordering reprints can be found online: http://n.neurology.org/subscribers/advertise